This is a competitive renewal with the broad objective of testing the Hypothesis: An autoimmune mechanism directed towards neuronal GluR subunits, associated with an inflammatory environment, contributes to neurodegenerative disorders such as Rasmussens encephalitis (RE). A hallmark of many neurodegenerative diseases is the extraordinary specificity through which disease progresses in the nervous system. In the past funding period we have examined immune dysfunction in this process through: 1) identifying autoantibodies to several GluR subunits in patients with neurodegenerative disease; 2) demonstrating their efficacy in directly altering receptor function; 3) identifying two mechanisms through which GluR antigens can escape tolerance; and 4) characterizing the interactions between autoantibodies and their target protein at the molecular and structural level. To determine how the inflammatory environment, as would be present in the microglial nodule, affects neuronal susceptibility to excitotoxicity, we developed a tissue culture system for exploring the mechanisms of cytokine-mediated changes in neuronal response. An ongoing aspect of this study is based upon the preliminary results that prolonged exposure of neurons to the inflammatory cytokine TNFalpha alters the expression of non-NMDA G1uR subunits. This renewal will continue to examine the neuronal response to an inflammatory environment and how this environment affects neuronal survival, both in response to excitotoxins and to anti- GluR antibodies as found in patients with RE and other neurodegenerative diseases. In Specific Aims 1 and 2 we will determine the effects of inflammatory cytokines and microglia on neuronal remodeling of G1uR expression and function. In Specific Aims 3-5 we determine the mechanisms (including gene transcription, translation, assembly and degradation) that are used by the neuron to respond to the inflammatory environment and accomplish remodeling of GluR expression and function. Finally, in Specific Aims 6 and 7, we develop subunit-specific monoclonal antibodies (mAb) that act as highly specific GluR agonists and receptor modulators to determine their effect on neuronal viability when inflammation and subunit-specific agonist-like autoreactivity to GluRs occur simultaneously, as is present in RE.